Physical signs and atherosclerotic cardiovascular disease in familial hypercholesterolemia: the HELLAS-FH Registry.

AIMS: Three physical signs, namely tendon xanthomas, corneal arcus and xanthelasma, have been associated with heterozygous familial hypercholesterolemia (heFH). The prevalence and clinical significance of these signs are not well established among contemporary heFH individuals. This study explored the frequency as well as the association of these physical signs with prevalent atherosclerotic cardiovascular disease (ASCVD) in heFH individuals. METHODS: Data from the Hellenic Familial Hypercholesterolemia Registry were applied for this analysis. The diagnosis of heFH was based on the Dutch Lipid Clinic Network Score. Multivariate logistic regression analysis was conducted to examine the association of heFH-related physical signs with prevalent ASCVD. RESULTS: Adult patients ( n  = 2156, mean age 50 ±â€Š15 years, 47.7% women) were included in this analysis. Among them, 14.5% had at least one heFH-related physical sign present. The prevalence of corneal arcus before the age of 45 years was 6.6%, tendon xanthomas 5.3%, and xanthelasmas 5.8%. Among physical signs, only the presence of corneal arcus before the age of 45 years was independently associated with the presence of premature coronary artery disease (CAD). No association of any physical sign with total CAD, stroke or peripheral artery disease was found. Patients with physical signs were more likely to receive higher intensity statin therapy and dual lipid-lowering therapy, but only a minority reached optimal lipid targets. CONCLUSION: The prevalence of physical signs is relatively low in contemporary heFH patients. The presence of corneal arcus before the age of 45 years is independently associated with premature CAD.

Corneal arcus as the presenting sign of familial hypercholesterolemia in a young child.

A 2.6-year-old boy presented with prominent corneal arcus. This clinical sign is rarely seen at such a young age and led to the diagnosis of familial hypercholesterolemia (FH). Genetic analysis detected biallelic pathogenic sequence variants c.1069G>A and c.2034C>A in the LDLR gene. There is significant cardiovascular morbidity and mortality associated with FH, hence early diagnosis and treatment is imperative.

Cloudy Cornea with Arcus Juvenilis in a Case of Dense Deposit Disease.

A 25-year-old male patient presented with complaints of blurred vision in both eyes since 2 years. The patient was a known case of nephrotic syndrome with dyslipidaemia for which he was on diuretics and lipid-lowering agents for 3 years. On examination, his visual acuity was 6/9 in both eyes with cloudy cornea and arcus juvenilis. Fundus examination was within normal limits. On systemic work-up, his lipid profile was deranged with increased serum total cholesterol, very low density lipoprotein, low density lipoprotein and triglyceride. The serum high density lipoprotein was decreased. Renal function test revealed elevated serum creatinine with significant proteinuria. Renal biopsy was suggestive of dense deposit disease on immunofluorescence and transmission electron microscopy. Ocular manifestation of dense deposit disease is characterised by retinal drusen, pigmentary atrophy, choroidal neovascular membrane and atypical serous retinopathy. To the best of our knowledge, anterior segment changes in dense deposit disease has not been reported. This is the first case reporting cloudy cornea with arcus juvenilis in a case of dense deposit disease.

Is Corneal Arcus Independently Associated With Incident Cardiovascular Disease in Asians?

PURPOSE: To examine the longitudinal relationship between baseline corneal arcus (CA) and incident cardiovascular disease (CVD) in ethnic Indian and Malay adults in Singapore. DESIGN: Population-based cohort study. METHODS: Indian and Malay adults aged 40-80 years were recruited for baseline and 6-year follow-up visits between 2004-2009 and 2010-2015, respectively (follow-up response rate 73.9%). CA was assessed by ophthalmologists using slit-lamp biomicroscopy. The main outcome was self-reported incident CVD, defined as new myocardial infarction, angina pectoris, or stroke, which developed between baseline and follow-up. Multivariable logistic regression models assessed independent associations between baseline CA and incident CVD, adjusting for traditional CVD risk factors including age, sex, serum cholesterol, hypertension, diabetes, and smoking. We further conducted sex-stratified analyses to identify possible effect modifications. RESULTS: Of the total 3637 participants (overall mean [SD] age: 56 [9] years, 46% male) with available follow-up data, without history of CVD at baseline, 208 (5.7%) incident CVD cases were reported. Participants with CA were more likely to have incident CVD (7.5%) than those without (4.9%). After controlling for traditional CVD risk factors, CA was independently associated with incident CVD (odds ratio [95% confidence interval]: 1.52 [1.07-2.16]) in adjusted models. In sex-stratified models, associations between CA and incident CVD were seen in men (1.73 [1.12-2.67]) and not in women (1.05 [0.56-1.97]). CONCLUSIONS: CA is associated with incident CVD, independent of serum lipids and traditional CVD risk factors, in ethnic Malay and Indian men. Our finding suggests that CA is an additional observable indicator of CVD in men.

Association Between Cholesterol Efflux Capacity and Atherosclerotic Cardiovascular Disease in Patients With Familial Hypercholesterolemia.

OBJECTIVE: Patients with familial hypercholesterolemia (FH) are at high risk for premature atherosclerotic cardiovascular disease (ASCVD), especially because of long-term exposure to high low-density lipoprotein cholesterol levels. It has been reported that low-density lipoprotein-lowering therapy delays the onset of ASCVD. However, it still remains difficult to prevent it. Therefore, novel biomarkers and therapeutic targets are necessary to evaluate and prevent atherosclerosis in FH. The aim of this study was to investigate associations of cholesterol efflux capacity with the presence of ASCVD and clinical features in patients with heterozygous FH. APPROACH AND RESULTS: We measured cholesterol efflux capacity in 227 patients with heterozygous FH under pharmaceutical treatment. Seventy-six (33.5%) of them were known to have ASCVD. In a logistic-regression analysis adjusted for risk factors, increased efflux capacity was associated with decreased risk of ASCVD even after the addition of high-density lipoprotein cholesterol level as a covariate (odds ratio per 1-SD increase, 0.95; 95% confidence interval, 0.90-0.99; P<0.05). Decreased cholesterol efflux capacity was associated with the presence of corneal arcus after adjusting for age and sex. In addition, inverse relationships between cholesterol efflux capacity and Achilles tendon thickness, as well as carotid intima-media thickness, were observed after adjustment for age, sex, and traditional cardiovascular risk factors. CONCLUSIONS: Cholesterol efflux capacity was independently and inversely associated with the presence of ASCVD in heterozygous FH. In view of residual risks after treatment with statins, cholesterol efflux capacity might be a novel biomarker and a therapeutic target for preventing atherosclerosis in patients with FH.

Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society.

AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH. METHODS AND RESULTS: Early diagnosis of HoFH and prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH. We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensive ACVD evaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years, or less if deemed necessary. CONCLUSION: This EAS Consensus Panel highlights the need for early identification of HoFH patients, prompt referral to specialized centres, and early initiation of appropriate treatment. These recommendations offer guidance for a wide spectrum of clinicians who are often the first to identify patients with suspected HoFH.

Corneal arcus and xanthomas in homozygous familial hypercholesterolemia: first report from China.

We report the case of a 12-year-old male who developed corneal arcus and multiple skin lesions with a 10-year history of xanthomas. The lesions appeared over his fingers, hands, elbows, knees, buttocks and feet. Laboratory studies showed a total serum cholesterol level of 752.1 mg/dL; a triglyceride level of 96.6 mg/dL; a low-density lipoprotein cholesterol level of 661.3 mg/dL. Findings were consistent with homozygous familial hypercholesterolemia. To our knowledge, this is the first such case to be reported from China.

Polymorphism at the TRIB1 gene modulates plasma lipid levels: insight from the Spanish familial hypercholesterolemia cohort study.

BACKGROUND AND AIMS: rs17321515 SNP has been associated with variation in LDL-C, high density lipoprotein cholesterol and triglycerides concentrations. This effect has never been studied in patients with severe hypercholesterolemia. Therefore, our aims were to assess the association of the rs17321515 (TRIB1) SNP with plasma lipids concentrations and anthropometric variables and to explore the interaction between this SNP and some classic risk factors in patients with familial hypercholesterolemia (FH). METHODS AND RESULTS: rs17321515 SNP was genotyped in 531 subjects with genetic diagnosis of FH. Homozygous A/A had significantly higher waist circumference compared with G/G subjects (P = 0.006) and carriers of the minor allele G (P = 0.039). Interestingly, smokers homozygous for the A allele displayed higher plasma triglycerides concentrations (P = 0.029), higher VLDL-C levels (P = 0.023) and higher TC/HDL-C ratio (P = 0.035) than carriers of the minor allele G. In addition, homozygous A/A with the presence of arcus cornealis displayed lower plasma ApoA-I levels (P = 0.024) and higher TC/HDL-C ratio (P = 0.046) than carriers of the minor allele G. CONCLUSIONS: Smoking status and presence of arcus cornealis modulate the effect of rs17321515 (TRIB1) polymorphism on plasma lipids levels in patients with FH. These results could explain the differences in the susceptibility to coronary heart disease in these patients.

Moderate phenotypic expression of familial hypercholesterolemia in Tunisia.

BACKGROUND: Autosomal Dominant Hypercholesterolemia (ADH) is an autosomal dominant disease caused by mutations in the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Xanthomas and coronary heart diseases (CHD) at an early age are the major clinical manifestations of the disease. METHODS: 16 families with familial hypercholesterolemia from different regions in Tunisia participated in the study. Mutations within the LDLR gene were screened through DNA sequencing. Lipids values were measured by standard enzymatic methods. RESULTS: We present here thirty five homozygotes and fifty six heterozygotes. Homozygotes presented extensive xanthomatosis, variable clinical manifestations of CHD, and total cholesterol levels in males and females of 17.26+/-4.18 and 17.64+/-2.59 mmol/L respectively. HDL-cholesterol levels were 0.62+/-0.24 and 1.00+/-0.61 mmol/L for males and females, respectively. None of the heterozygotes had tendon xanthomas (except for one female aged 62), eight had corneal arcus, and nine developed CHD mean between 46 and 88 years old. Total cholesterol levels in males and females ranged from 4.60 to 8.90 and from 4.30 to 10.50 mmol/L, respectively. CONCLUSION: Tunisian FH heterozygotes are characterized by a moderate clinical and biological expression of the disease.

Skin manifestations in familial heterozygous hypercholesterolemia.

Familial hypercholesterolemia, a form of primary hyperlipoproteinemia, is an autosomal dominant disorder characterized by an increase in serum LDL cholesterol concentrations. Multiple types of xanthomas occur, such as tendinous, tuberous, subperiosteal, and xanthelasma. Intertriginous xanthomas are rare, but if present are pathognomonic in this disorder. We report a patient with multiple xanthomas including the very rare intertriginous variety.

Relation of corneal arcus to cardiovascular disease (from the Framingham Heart Study data set).

Corneal arcus is a lipid-rich deposit at the corneoscleral limbus that shares some similarities with the lipid deposition of atherosclerosis. Epidemiologic studies examining the association between corneal arcus and coronary artery disease (CAD) have yielded mixed results. This study was conducted to determine if corneal arcus is an independent risk factor for cardiovascular disease (CVD) and CAD. A prospective analysis was performed using Cox proportional-hazards regression models in the Framingham Heart Study Original Cohort and Offspring Cohort database. This cohort included 23,376 patient-examinations, during 3,890 (17%) of which corneal arcus was identified. Corneal arcus was a predictor of CVD and CAD at 4 years (hazard ratios [HRs] 2.28 and 1.99, respectively) and 8 years (HRs 2.52 and 2.35, respectively) of follow-up (p <0.0001 for all). Corneal arcus was no longer predictive of either CVD or CAD, however, after adjustment for age and gender at 4 years (HRs 1.07 and 1.01, respectively) and 8 years (HRs 1.18 and 1.17, respectively) of follow-up (p >0.05 for all). In conclusion, corneal arcus predicted CVD and CAD in the community-based Framingham Heart Study cohort because of the strong association of corneal arcus with increasing age. To date, this is the largest and lengthiest population-based cohort study examining the direct association between corneal arcus and CVD and CAD.

Familial hypercholesterolaemia: the Cape Town experience.

Familial hypercholesterolaemia (FH), an autosomal dominantly inherited disorder characterised by elevated plasma low-density lipoprotein (LDL) cholesterol levels, tendon xanthomata and premature ischaemic heart disease, is amenable to treatment with modern medication. The clinical and biochemical details of 1 031 patients with FH were analysed. FH is the most common monogenic disorder of lipoprotein metabolism presenting to the Lipid Clinic at Groote Schuur Hospital, accounting for about 20% of consultations. The hospital classified 55% of the FH patients as white, 43% as coloured, 1.5% as Asian and 0.5% as black. In the FH cohort (whose mean age at presentation was 44 years), 80% had tendon xanthomata, 36% had arcus cornealis, and 14% had xanthelasma. Tendon xanthomata was present in almost 90% of patients by the age of 50 years. Arcus cornealis was present in about 45% by the age of 40 years, further increasing in frequency with age. Cardiovascular complications included ischaemic heart disease (43%), stroke (1.5%), transient ischaemic attacks (1.3%), and peripheral vascular disease (3.7%). The mean age of death was 55 (+/-13) years; 51 ( +/-10) years in men and 61 ( +/-12) years in women. In 46% of the cohort, a defective gene was identified by testing for locally prevalent mutations.